Manglio Miguel Rizzo

Los inhibidores de tirosina quinasa (TKI) han revolucionado el tratamiento del cáncer de pulmón de células no pequeñas (CPCNP) con alteraciones genéticas específicas, como la translocación de ALK. Sin embargo, su impacto en el sistema inmunológico y su asociación con infecciones oportunistas, como la tuberculosis (TB), sigue siendo poco explorado. Caso clínico: Varón de 53 años con CPCNP ALK-positivo, estadio IV por compromiso pleural, inició tratamiento con brigatinib, mostrando respuesta parcial a los 3 meses. Al quinto mes, presentó fiebre persistente, linfopenia grado 1 y derrame pleural derecho. Los estudios histopatológicos revelaron pleuritis granulomatosa necrotizante compatible con TB, a pesar de ausencia de antecedentes tuberculosos. Los cultivos y tinciones para micobacterias fueron negativos, pero se inició tratamiento antituberculoso empírico con esquema de 4 drogas. Brigatinib fue reemplazado por alectinib para evitar hepatotoxicidad por los antifímicos. El paciente mostró mejoría clínico-radiológica de la TB. Este reporte subraya la necesidad de vigilancia activa para infecciones oportunistas en pacientes tratados con TKI, incluso en ausencia de inmunosupresión tradicional. Se recomienda evaluación de TB latente previa al tratamiento en áreas endémicas y monitorización estrecha de síntomas sugestivos. Futuros estudios deben clarificar el riesgo real y estrategias profilácticas en este contexto.

Hypoxia is a hallmark of solid tumors, driving metabolic reprogramming and immune evasion. In lung cancer, hypoxia-induced activation of carbonic anhydrase IX (CAIX) promotes lactate accumulation and extracellular acidification, fostering an immunosuppressive tumor microenvironment (TME). Analysis of public datasets revealed that patients with high CAIX expression exhibited significantly reduced median survival (p < 0.001). Moreover, CAIX correlated with HIF-1α, PD-L1, and immunosuppressant molecules, linking hypoxia-driven metabolic alterations with immune dysfunction. Here, we evaluated the capacity of 4-methylumbelliferone (4Mu) to counteract these effects and enhance antitumor immunity. In vitro, hypoxia increased CAIX and monocarboxylate transporter -4 (MCT4) expression in lung carcinoma cells, elevated lactate release, and reduced extracellular pH while promoting an M2-like macrophage profile and impairing antigen-specific splenocyte proliferation (p < 0.01). Treatment with 4Mu downregulated CAIX expression, restored extracellular pH, decreased lactate secretion, and rescued lymphocyte proliferation (p < 0.01). In vivo, 4Mu reduced CAIX expression, shifted macrophage polarization toward a pro-inflammatory phenotype, and enhanced CD8+ T cell infiltration. 4Mu was safe and well tolerated, and notably, combined with anti-PD-1 therapy, it synergistically inhibited tumor growth and increased both CD4+ and CD8+ T cell infiltration. These findings support 4Mu as a metabolic modulator capable of mitigating CAIX-driven acidosis and improving the efficacy of immunotherapy in lung cancer.

PURPOSE: In Argentina, anaplastic lymphoma kinase (ALK) gene rearrangements occur in approximately 6.1% of non–small cell lung cancer (NSCLC) cases. Given the availability of second- and third-generation ALK inhibitors, real-world data are needed to inform optimal treatment strategies. However, access to these therapies remains limited for many patients. METHODS: We conducted a multicenter retrospective study of patients with metastatic ALK-positive NSCLC (ALKp) treated with first-line tyrosine kinase inhibitors (TKIs) from January 2014 to February 2024. Demographics, treatment patterns, clinical outcomes, and factors affecting treatment accessibility were analyzed. RESULTS: We identified 104 patients with ALKp. The median age was 55 years (IQR, 45-67); 86% had Eastern Cooperative Oncology Group ≤1, 58% were women, and 57% were nonsmokers. Brain metastases were present at diagnosis in 29%, with 50% receiving local treatment. First-line TKIs included alectinib (42%), crizotinib (30%), lorlatinib (16%), and brigatinib (12%). Crizotinib use was frequently due to limited access to new-generation TKIs. Adverse events occurred in 54%, with 21% grade 3 to 4. The objective response rate was 73%. At a median follow-up of 42 months, 48% experienced progression. Crizotinib was associated with higher risk of progression or death compared with newer TKIs (hazard ratio, 3.09 [95% CI, 1.75 to 5.5]; P = .01). CNS progression occurred in 18%, more often with crizotinib (42% v 8%, P = .04). Among those progressing, 82% received second-line therapy, most commonly lorlatinib or alectinib. The overall survival at 24 months was 81%, with 27% of patients deceased at data cutoff. CONCLUSION: This real-world study describes outcomes and treatment patterns among patients with ALKp in Argentina. It highlights disparities in access to optimal therapies and reinforces the need for equitable access to new-generation ALK inhibitors to improve clinical outcomes.

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy characterized by a complex tumor microenvironment (TME) that plays a critical role in disease progression and therapeutic resistance. Tumor-infiltrating immune cells, including T lymphocytes, macrophages, dendritic cells, and myeloid-derived suppressor cells, exhibit dual functions, either promoting or suppressing tumor growth depending on their phenotype and interactions within the TME. The presence of immune evasion mechanisms, such as the loss of human leukocyte antigen (HLA) expression, upregulation of immune checkpoint molecules, and metabolic reprogramming (hypoxia-induced glycolysis and lactate accumulation), further contributes to immune suppression and poor treatment responses. While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of recurrent/metastatic HNSCC, response rates remain highly variable, underscoring the need for biomarker-driven patient selection and combinatorial therapeutic strategies. This review provides a comprehensive analysis of the role of immune cells in the TME of HNSCC, discusses the mechanisms underlying immune escape, and explores emerging immunotherapeutic and epigenetic-targeting approaches aimed at enhancing antitumor immune responses and improving clinical outcomes.

Las fluoropirimidinas son quimioterápicos antimetabolitos usados en varios tipos de cáncer. El 5-fluorouracilo (5-FU) actúa inhibiendo la síntesis de ADN y ARN mediante sus metabolitos activos, que interfieren con la timidilato sintasa y se incorporan en los ácidos nucleicos, bloqueando así la proliferación celular. La eliminación de estas drogas depende de la enzima dihidropirimidina deshidrogenasa (DPD), codificada por el gen DPYD. Mutaciones en DPYD, presentes en un 3-7% de la población según lo reportado, pueden reducir la actividad de la DPD, lo que aumenta el riesgo de toxicidad grave al acumularse el 5-FU. La función de la DPD puede evaluarse mediante estudios genotípicos de DPYD o fenotípicos, como la medición de uracilemia. Esto permite ajustar las dosis para minimizar efectos adversos en pacientes con actividad reducida de la DPD, mejorando la seguridad del tratamiento.

Currently, therapy for early-stage human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) is based on the combination of trastuzumab and pertuzumab plus chemotherapy in a neoadjuvant regimen. The INMUNOHER study aimed to detect immunological markers in peripheral blood and their association with treatment response. Sixty-two HER2+ BC patients were recruited. Pre-treatment samples were obtained before the start of treatment, while post-treatment samples were obtained after completing therapy and before surgery and were analyzed by flow cytometry. The pathologic complete response (pCR) rate achieved was 82.3%. The expression of the NKp30, PD-1, and TIM-3 receptors was reduced in the Natural Killer (NK)-CD56dim subset of patients who did not achieve pCR. Following therapy, many changes were found in leukocytes, including alterations in T cell lymphocyte proportions. Also, the percentage of NK cells decreased, and several phenotypic changes were observed in this population. After treatment, IFN-γ production by NK cells against HER2+-cells with or without trastuzumab was significantly reduced. HER2-targeted therapy plus chemotherapy demonstrated high efficacy in most patients, reducing the statistical power for finding immunological markers. However, NK subset phenotypes correlated better with response groups, and numerous changes in the percentage of leukocytes and T and NK cells, as well as changes in the functionality of NK cells, were observed in most patients after treatment, encouraging further research into these immune populations.

We performed a systematic review and meta-analysis to assess the efficacy of EGFR-tyrosine kinase inhibitors (TKI) retreatment in advanced/metastatic non-small-cell lung cancer (NSCLC) patients. We systematically searched PubMed, Embase, Cochrane databases, ASCO, and ESMO websites for studies evaluating EGFR-TKI retreatment in advanced/metastatic NSCLC patients. All analyses were performed using R software (v.4.2.2). We included 19 studies (9 CTs and 10 retrospective cohorts) with a total of 886 patients. In a pooled analysis of all patients during retreatment with TKI, median OS was 11.7 months (95% confidence interval [CI] 10.2–13.4 months) and PFS was 3.2 months (95% CI 2.5–3.9 months). ORR was 15% (95% CI 10–21%) and DCR was 61% (95% CI 53–67%). The subanalysis by generation of TKI in the rechallenge period revealed a slightly better ORR for patients on 3rd generation TKI (p = 0.05). Some limitations include the high heterogeneity of some of the analyses and inability to perform certain subanalyses. Our results unequivocally support the benefit of EGFR-TKI rechallenge in EGFR-mutated NSCLC patients progressing on TKI treatment after a TKI-free interval. These findings may be especially valuable in areas where access to novel therapeutic drugs and clinical trials is limited.

Opinion Statement Strategies using immune checkpoint inhibitors (ICI), which can enhance antitumor immune responses, have revolutionized the lung cancer therapeutic landscape. The ICI mechanism of action involves the blockade of regulatory cell surface molecules using antibodies against the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) (ipilimumab, tremelimumab); the programmed death receptor-1 (PD-1; nivolumab, pembrolizumab); or the PD ligand-1 (PD-L1; atezolizumab, durvalumab). Notably, anti-PD-1 demonstrated long-term survival benefits, durable objective responses, and a manageable safety profile in patients with non-small cell lung cancer (NSCLC). The combination of anti-PD1 or anti-PD-L1 and platinum chemotherapy achieved better survival outcomes than chemotherapy alone, which was observed irrespective of PD-L1 expression on cancer cells. Although promising results have been reported from large clinical trials, especially for patients with high PD-L1 expression, the optimal treatment approach for patients with PD-L1-negative NSCLC has yet to be defined. We propose a guide for clinicians in the therapeutic decision-making process based on the latest data available about treatments, prognostic factors, predictive biomarkers, and real-world evidence in PD-L1-negative NSCLC patients.

Adaptive NK cells constitute an NK cell subpopulation, which expands after human cytomegalovirus (HCMV) infection. This subpopulation has stronger production of cytokines after CD16 stimulation, longer life and persistence than conventional NK cells and are, therefore, interesting tools for cancer immunotherapy. Since there is limited information on adaptive NK cells in cancer patients, we described this population phenotypically and functionally, by flow cytometry, in the context of HER2 + breast cancer (BC) directed therapy. We assessed HCMV status in 78 patients with BC. We found that, similarly to healthy donors (HD), a high proportion of BC patients were HCMV-positive, and nearly 72% of them had an adaptive NK cell subpopulation characterized by the loss of FcεRIγ intracellular adaptor protein or the presence of NKG2C receptor. However, in BC patients, FcεRIγ− and NKG2C + NK cell populations overlapped to a lesser extent than in HD. Otherwise, no profound phenotypic differences were found between BC patients and HD. Although FcεRIγ− or NKG2C + NK cell subsets from BC patients produced more IFN-γ than their FcεRIγ + or NKG2C− NK cell counterparts, IFN-γ production increased only when NK cells simultaneously expressed FcεRIγ− and NKG2C + , whereas in HD the presence of NKG2C marker was sufficient to display greater functionality. Furthermore, in a group of patients treated with chemotherapy and Trastuzumab plus Pertuzumab, FcεRIγ-NKG2C + and FcεRIγ-NKG2C− NK cells retained greater functionality after treatment than FcεRIγ + NKG2C− NK cells. These results suggest that the presence or magnitude of adaptive NK cell subsets might serve as a key determinant for therapeutic approaches based on antibodies directed against tumor antigens.